Biomedical subjects

F Demenais

Publications and source records attributed to F Demenais.

At least 19 recordsLinked to original sources

PubMed2005

Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma.

OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.

Cell Line, Tumor↗

PubMed2005

Genome screen in the French EGEA study: detection of linked regions shared or not shared by allergic rhinitis and asthma.

In the sample of 295 French EGEA families with at least one asthmatic subject, a genome screen was conducted to identify potential linkage regions specific either to allergic rhinitis (AR) or to asthma as well as those shared by the two diseases. Two binary rhinitis phenotypes based on (1) diagnosis (ARbin1) and (2) symptoms (ARbin2) and a categorical ordered trait (ARcat) were considered. Asthma phenotype was based on answers to a standardized questionnaire plus the presence of bronchial hyper-responsiveness. Linkage analyses were conducted using the maximum likelihood binomial (MLB) method. These analyses provided potential evidence for linkage to three regions in the whole sample: 1p31 for the phenotype defined by ARbin2 plus asthma (P=0.00016), 2q32 for ARbin2 (P=0.00016) and 3p24-p14 for ARcat (P=0.001). Two other regions were detected in the subset of 185 families with at most one asthmatic sib: 9p22 and 9q22-q34 for ARbin1 (P=0.001 and 0.0007, respectively). No region showed evidence for linkage to asthma without being also linked to AR. While 1p31 may contain a genetic determinant common to asthma and AR, 2q32, 3p24-p14, 9p22 and 9q22-q34 are more likely to harbor genetic factors specific to AR.

Asthma↗

PubMed2003

Indication of linkage and genetic heterogeneity for asthma and atopy on chromosomes 8p and 12q in 107 French EGEA families.

Using the sample of 107 families with at least two asthmatic siblings, as part of the EGEA study, we have investigated linkage to asthma (or atopy) and genetic heterogeneity according to the presence/absence of atopy (or asthma) using two approaches: (1) the triangle test statistic (TTS), which considers the identical by descent (IBD) distribution among affected sib-pairs discordant for another associated phenotype (eg asthmatic sib-pairs discordant for atopy) and (2) the predivided sample test (PST), which compares the IBD distribution of marker alleles between affected sib-pairs concordant and discordant for the associated phenotype. Two regions, 8p and 12q, already reported to be linked to both asthma and atopy, were examined here. A total of 20 asthmatic sib-pairs discordant for atopy and 24 atopic pairs discordant for asthma were analyzed by both TTS and PST methods and 83 pairs with atopic asthma by PST. Some evidence for linkage was observed for two markers in the 8p23.3-p23.2 region; D8S504 for asthma with genetic heterogeneity according to the presence/absence of atopy and D8S503 for atopy with genetic heterogeneity according to the presence/absence of asthma. In the 12q14.2-q21.33 region, there was also some evidence of linkage to two markers, D12S83 and D12S95, for atopy and asthma, respectively, with genetic heterogeneity according to the presence/absence of the associated trait. Provided the small distance between the two markers on either 8p (16 cM) or 12q (21 cM), it is unclear whether one or two genetic factors are involved in either region.

Asthma↗

PubMed2003

Segregation analysis of prostate cancer in France: evidence for autosomal dominant inheritance and residual brother-brother dependence.

Four segregation analyses concerning prostate cancer (CaP), three conducted in the United States and one in Northern Europe, have shown evidence for a dominant major gene but with different parameter estimates. A recent segregation analysis of Australian pedigrees has found a better fit of a two-locus model than single-locus models. This model included a dominantly inherited increased risk that was greater at younger ages and a recessively inherited or X-linked increased risk that was greater at older ages. Recent linkage analyses have led to the detection of at least 8 CaP predisposing genes, suggesting a complex inheritance and genetic heterogeneity. To assess the nature of familial aggregation of prostate cancer in France, segregation analysis was conducted in 691 families ascertained through 691 CaP patients, recruited from three French hospitals and unselected with respect to age at diagnosis, clinical stage or family history. This mode of family inclusion, without any particular selection of the probands, is unique, as probands from all previous analyses were selected according to various criteria. Segregation analysis was carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts. Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency of 0.03%) with an additional brother-brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at-risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. This study supports the model of Mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrates that additional genetic and/or common sibling environmental factors are involved to account for the familial clustering of CaP.

Age of Onset↗

PubMed2002

Regressive threshold model for familial analysis of complex diseases with variable age of onset.

Few models for segregation (or combined segregation-linkage) analysis have been developed to account for variable age of onset. The unified model (UM) can only take into account age at examination. In the logistic hazard model (LHM), Abel and Bonney ([1990] Genet. Epidemiol. 7:391-407) incorporated survival analysis concepts into the regressive logistic model of Bonney ([1986] Am. J. Med. Genet. 18:731-749), but interpretation of familial dependence parameters is difficult. In this article, we extended the regressive threshold model (RTM) proposed by Demenais ([1991] Am. J. Hum. Genet. 49:773-785) to account for a variable age of onset of complex diseases. This model assumes an underlying liability to disease and is more general than the original logistic formulation, since the phenotypes of each individual's antecedents can be adjusted for their own genotypes and covariate effects. The variation of risk with age can be expressed as a general step function, and variants of the model have been proposed by imposing different types of constraints among the time-dependent thresholds. The performances of the three models (UM, LHM, and RTM) were compared in the context of segregation analysis of family data generated with variable age of onset. All analysis models were robust with respect to false conclusion of a major gene, and the best results were obtained under RTM. The power to detect the major gene was higher under LHM than RTM, but the best fit of the estimated cumulative age-dependent penetrance with respect to the true value was obtained under RTM. This new model may thus prove helpful in contributing to identification of genes underlying complex diseases, since it can easily include linked marker loci and linkage disequilibrium.

Age of Onset↗

PubMed2001

Sporadic multiple primary melanoma cases: CDKN2A germline mutations with a founder effect.

Multiple primary cancers are one of the hallmarks of inherited predisposition. Outside the familial context, multiple primary tumors could be related either to germline de novo mutations or to low-penetrance mutations, in predisposing genes. We selected 100 patients who displayed multiple primary melanoma (MPM) without any known melanoma cases recorded within their families and looked for germline mutations in the two melanoma-predisposing genes identified to date, CDKN2A and CDK4 exon 2. Nine patients (9%) had germline mutations in CDKN2A, whereas none carried germline mutations in exon 2 of CDK4. Seven cases displayed a recurrent missense mutation, G101W, already described in more than 20 melanoma-prone families; one case carried a missense mutation never reported to date (P114S), and the last case was a carrier of a 6 bp insertion at nucleotide 57 resulting in a duplication of codons 18 and 19. To ascertain whether the G101W was a mutational hot spot for de novo mutations or a common founder mutation, we genotyped eight microsatellite markers flanking the CDKN2A gene. After allowing for recombination over time, haplotype sharing provided evidence for an original G101W mutation common to 6 out of 7 sporadic MPM cases. Therefore, it can be concluded that de novo germline CDKN2A mutations associated with MPM are rare.

Adult↗

PubMed2001

Detection of parent-of-origin effects for atopy by model-free and model-based linkage analyses.

Parent-of-origin effects for atopy were investigated by a model-free affected sib-pair (ASP) method and two model-based approaches in the Busselton nuclear families. Among the regions showing potential linkages to atopy by the ASP method, a significant excess of paternal allele sharing as compared with maternal allele sharing was observed for a cluster of three markers on chromosome 13. The two model-based methods, which specify either sex-specific recombination rates or different penetrances for heterozygotes according to the parental origin of disease allele (imprinting), led to the same results, both suggesting a paternal effect. Thus, these two ways of modelling parent-of-origin effects appear equivalent in nuclear family data. Further simulations are needed to investigate whether the mechanisms underlying parent-of-origin effects can be distinguished in larger pedigree structures.

Adult↗

PubMed2001

Indication of linkage and genetic heterogeneity of asthma according to age at onset on chromosome 7q in 107 French EGEA families.

It is generally believed that an early age at the onset of disease is associated with a stronger genetic component. Our aim here was to investigate both linkage and genetic heterogeneity of asthma, the latter corresponding to different genotype relative risks of a putative linked gene according to age at onset of asthma. This analysis was conducted in 107 French EGEA families with at least two asthmatic siblings, considering 157 markers that were part of our previous genome screen, using the TTS (the Triangle Test Statistic) which has been developed to detect both linkage and intra-sibpair genetic heterogeneity. This test has been applied to 38 asthmatic sib-pairs discordant for age at the onset of asthma. To confirm the existence of genetic heterogeneity, we also used the predivided sample test (PST) which compares the IBD (identity by descent) distribution of marker alleles between asthmatic sib-pairs concordant (67) and discordant (38) for the age at onset. The cutoff point used for the age at onset was 4 years, the median age at onset in our sample of asthmatic sibs. Linkage and genetic heterogeneity for a region located on chromosome 7q (at 109 cM from pter) were indicated by both tests, TTS (P=0.005, P>0.5 after correction for multiple testing) and PST (P=0.0001, 0.015 after correction). These results suggest a genetic factor on 7q involved in asthma with genotype relative risks differing according to age at onset of disease.

Age of Onset↗

PubMed2001

Association between germ cell tumours, large numbers of naevi, atypical naevi and melanoma.

Identifying groups of subjects at high risk for the development of melanoma is crucial for the early diagnosis of curable tumours. In the present study, we performed a skin examination in a group of 63 patients followed up after treatment of germ cell tumours (GCTs) who were referred to the dermatologist for multiple pigmented cutaneous spots. Forty-nine patients bearing a great number of naevi or atypical naevi were included in the study. Two thin cutaneous melanomas were discovered in two patients. In addition, a third patient had had a conjunctival melanoma since treatment of the GCT. Our study confirms the presence of atypical naevi in a subgroup of GCT patients, who are shown to be at high risk of developing melanoma. Patients harbouring multiple pigmented spots should be referred for a skin examination aimed at early detection of curable melanomas, and should be advised to protect themselves from sun exposure.

Adolescent↗

PubMed2001

[Epidemiological study of genetic and environmental factors in asthma, bronchial hyperresponsiveness and atopy. Protocol and potential selection bias].

BACKGROUND: The EGEA study combines a case-control study and a family study to assess genetic and environmental risk factors and their interactions for asthma, bronchial hyperresponsiveness and atopy. Information is scanty regarding potential selection biases, in particular regarding familial ressemblance in epidemiological surveys of this kind. METHODS: Asthmatic probands (adult and paediatric) were recruited in chest clinics of six clinical centres. Controls were mostly population-based (electoral rolls) for adults and recruited in surgery departments for children. RESULTS: The population examined includes 348 nuclear families ascertained by one asthmatic and 416 controls, totalling 1847 subjects (EGEA I) and an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II). Potential biases for the various types of analyses have been studied. Quantification of the consequences of the greater participation of probands with a parental history of asthma shows it does not introduce a major bias in the estimates of familial resemblance. Cases and controls showed a good comparability regarding sex, age, area of residence and familial geographical origin, allowing proper associations studies for environmental and candidate genetic factors. CONCLUSIONS: The case-control component of the study will allow to perform studies on environmental factors and association studies for various genetic polymorphisms. Using the family base collected, segregation and genetic linkage/association analyses with DNA markers may be performed.

Adult↗

PubMed2000

Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma).

The main objective of this study was to search for a major gene controlling total serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and allergy. We studied 335 French nuclear families of the EGEA study (Epidemiological study of the Genetics and Environment of Asthma), ascertained through asthmatic probands (123 are parents in the family, 212 children). Segregation analyses were performed by regressive models, which can take into account a major gene effect, various sources of familial covariation (genetic and/or environmental) as well as measured risk factors (i.e. , age, sex, smoking habits). Different strategies were considered to account for the mode of ascertainment of the families through a correlated trait (asthma): the ascertainment mode was either ignored (strategy A) or taken into account by adjusting IgE levels for the position in the family, i.e., probands, blood relatives, spouses (strategy B) or excluding the asthmatic children-probands and computing the likelihood of each family conditionally on parents' IgE levels (strategy C). Whereas a major gene effect could not be detected with strategy A, strategies B and C showed evidence for the transmission of a dominant major gene for high IgE levels, which was more significant with strategy B. This gene does not interact with any of the covariates and is responsible for approximately 15% of IgE variation (the allele frequency is 0.65).

Adolescent↗

PubMed2000

Genome screen for asthma and related phenotypes in the French EGEA study.

A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.

Adolescent↗

PubMed2000

Patterns of familial aggregation of three melanoma risk factors: great number of naevi, light phototype and high degree of sun exposure.

BACKGROUND: Besides melanoma susceptibility genes and shared environmental exposures, part of the familial clustering of cutaneous malignant melanoma (CMM) might be due to familial aggregation of melanoma-associated phenotypes. Our goal was to assess the patterns of familial aggregation of three melanoma risk factors: great number of naevi (GNN), light phototype (LP) and high degree of sun exposure (HDSE). METHODS: Familial aggregation of GNN, LP and HDSE was investigated in 66 French families with at least two CMM cases and was measured by the asssociation of the relatives' traits with the probands' traits, using the generalized estimating equations approach. The probands were the melanoma cases leading to ascertainment of the families, subdivided into cases (with the trait studied) and controls (without the trait). RESULTS: We found significant evidence for familial aggregation of GNN only among sibs (OR = 3.7, 95% CI : 1.4-10.5, P = 0.01), of LP among blood relatives (OR = 3.8, 95% CI : 1.8-8.0, P = 0.004) and of HDSE among blood relatives (OR = 4.5, 95% CI : 2.1-9.9, P < 0.001) and spouses (OR = 44.3, 95% CI : 5.1-382.2, P < 10(-3)). These results suggest that genetic factors might account for the clustering of GNN and LP and shared environment for the aggregation of HDSE. The GNN clustering was lower in families with increasing numbers of CMM (>/=3 cases) or presence of p16 mutations, the opposite being observed for LP and HDSE. Moreover, the familial aggregation of LP was significantly lower in families with highly sun-exposed members. CONCLUSION: Melanoma might not only result from specific genetic and environmental factors but also from those underlying melanoma-associated traits involving complex gene-gene and gene-environment interactions.

Adult↗

PubMed2000

Gene-covariate interaction between dysplastic nevi and the CDKN2A gene in American melanoma-prone families.

The CDKN2A gene has been implicated in cutaneous malignant melanoma pathogenesis. Although CDKN2A mutations confer substantial risk for melanoma, clinicoepidemiological covariates including dysplastic nevi (DN), total nevi, and solar injury also enhance melanoma risk. To examine the relationship between CDKN2A and these three risk factors, we conducted combined segregation/linkage analysis using the class D regressive logistic model, as implemented in the computer program REGRESS. Genetic and covariate data were collected on 20 American melanoma-prone families, 13 of which had cosegregating CDKN2A mutations. Two types of analyses were conducted. The missing-indicator method used a missing-value indicator, set to 1 for unknown and 0 for known covariate status, and a second variable set to 1 for exposed and 0 for unexposed or unknown. The second method, complete-cases method, coded subjects with missing covariates as unknown for the affection status. The results for both analyses were very similar. Overall, there was a significant improvement in the likelihood when DN, total nevi or both covariates were added to the base model, which included dominant transmission of the CDKN2A gene and a linear increase of risk with the logarithm of age on the logit scale. In contrast, inclusion of solar injury did not significantly improve the likelihood for the base model. Significant evidence for a gene-covariate interaction was detected between DN and CDKN2A when DN was the only covariate in the model (missing-indicator method or complete-cases method) or when both DN and total nevi were in the model (complete-cases method only). Interestingly, in both methods, the odds ratio (OR) for DN was greater in subjects without mutations (OR, 20.1; 95% confidence interval, 4.8-92.8) versus those with CDKN2A mutations (OR, 3.3; 95% confidence interval, 1.1-10.0; complete-cases method). The CDKN2A-DN interaction illustrates the complex etiology of melanoma and needs to be confirmed in a larger sample of families.

Adolescent↗

PubMed1999

Indication of linkage of serum IgE levels to the interleukin-4 gene and exclusion of the contribution of the (-590 C to T) interleukin-4 promoter polymorphism to IgE variation.

Previous segregation analysis of a sample of 234 randomly selected Australian families showed evidence for a recessive major gene controlling serum immunoglobulin E (IgE) levels independently of the specific response to allergens (SRA). Since linkage has been recently reported between serum IgE levels and the 5q candidate region spanning the interleukin-4 (IL-4) gene, we investigated whether the recessive major gene detected by segregation analysis was linked to the IL-4 region and whether polymorphisms within the IL-4 gene were associated with IgE levels. Both sib-pair method and combined segregation and linkage analysis using the regressive models were applied to our data. Whereas there was no evidence of linkage of total IgE levels to the IL-4 region, an indication of linkage (P values ranging between 0.01 and 0.03) was found between IgE levels adjusted for SRA and two IL-4 polymorphisms: one dinucleotide repeat in intron 2 of the IL-4 gene and a single nucleotide (-590 C to T) polymorphism in the IL-4 promoter. However, the putative IL-4 linked gene did not appear to be in linkage disequilibrium with either of these two polymorphisms. A contribution of the IL-4 promoter polymorphism, presumed to be a potential functional variant influencing IgE variation, was also excluded.

Adolescent↗

PubMed1999

Segregation analysis of the specific response to allergens: a recessive major gene controls the specific IgE response to Timothy grass pollen.

Segregation analysis of the specific response to allergens (SRA) was performed in a sample of 234 randomly selected Australian families using the regressive models. Various SRA phenotypes were considered using broad and narrow definitions of these phenotypes, according to the type of test used, skin test or RAST test, and the specificity of the response to allergen. Strong evidence for familial dependencies among blood relatives was shown for most SRA phenotypes, especially when using a broad definition. There was no evidence for a Mendelian factor accounting for the familial transmission of these broadest phenotypes, which may involve multiple factors preventing the clear detection of a major effect with Mendelian transmission. However, segregation of a Mendelian recessive major gene was detected for one SRA sub-phenotype, the IgE response to a single allergen, Timothy grass pollen, measured by the RAST test. Identification of a specific SRA phenotype controlled by a major gene may have important implications for further linkage studies.

Adolescent↗

PubMed1999

Detection of quantitative trait loci associated with alcohol-dependence: use of model-free sib-pair method and combined segregation-linkage analysis based on regressive models.

Two linkage methods were used to detect loci underlying neurophysiological measures associated with alcohol dependence 1) the Haseman-Elston (H-E) sib pair method for genome-wide search, and 2) the combined segregation-linkage (CSL), based on regressive models, to confirm positive linkages found by the genome screening. Among 14 linkage results that were significant at the 0.5% level using H-E, the CSL method leads to similar p-values in only three cases but to higher p-values in all others. Investigation of these discrepancies shows that assumptions (normality and homoscedasticity of the error term) of H-E least-squares regression method are not verified. A robust estimator of slope parameters without assuming any distribution function for the linear model error terms increases the p-values and reduces the difference between H-E and CSL results. Alternatively, the CSL approach may lack power when multiple genes with small effects are involved.

Alcoholism↗

PubMed1999

Sib-pair linkage analysis of alcohol dependence taking into account covariates and age-of-onset variability: evaluation of the residual approach.

The construction of residuals allowed us to consider a phenotype related to alcohol dependence (ALDX1) adjusted for age, gender and current smoking status. Using the Haseman and Elston regression test, we compared genome scan results for detection of loci for the unadjusted and adjusted ALDX1 phenotypes in the Collaborative Study on the Genetics of Alcoholism (COGA) data. More markers were significant at the 1% level for the binary than for the residual analyses. Overall, our residual analyses do not show substantial improvement in their ability to detect linkage for alcohol dependence in the COGA data. This may be due to the relatively small sample size of discordant sib pairs.

Age of Onset↗